Long-Range Chemical Ligation from N!N Acyl Migrations in Tryptophan Peptides via Cyclic Transition States of 10- to 18- Members

Chemical ligations to form native peptides from N→N acyl migrations in Trp-containing peptides via 10- to 18-membered cyclic transition states are described. In this study, a statistical, predictive model that uses an extensive synthetic and computational approach to rationalize the chemical ligation is reported. N→N acyl migrations that form longer native peptides without the use of Cys/Ser/Tyr residues or an auxiliary group at the ligation site were achieved. The feasibility of these traceless chemical ligations is supported by the NC bond distance in N-acyl isopeptides. The intramolecular nature of the chemical ligations is justified by using competitive experiments and theoretical calculations.